Deciphering the roles of RIFIN and STEVOR parasite antigens in severe malaria pathogenesis via transcriptomics and immune profiling

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PROJECT SUMMARY Despite decades of research, Plasmodium falciparum malaria continues to kill hundreds of thousands of children in sub-Saharan Africa each year. Vulnerability to severe malaria is complex, involving both host and parasite factors. Blood type A is an established risk factor for severe malaria, whereas blood type O is associated with protection from complicated symptoms. The exact mechanism of this phenomenon is incompletely understood but may involve interactions mediated by particular parasite antigens. RIFINs and STEVORs are highly diverse parasite protein families that are displayed on the surface of infected red blood cells. Recent laboratory studies suggest that these antigens may exacerbate malaria severity through multiple mechanisms, including adherence to nearby red blood cells to form “rosettes” that envelop the parasite and protect it from immune clearance. Certain RIFINs bind preferentially to type A red blood cells. STEVORs have a similar binding preference for glycophorin C, another red blood cell surface protein. These intriguing findings suggest that RIFINs and STEVORs may be central to P. falciparum virulence and drive differences in susceptibility to severe disease between blood types. Despite promising in vitro links to severe malaria vulnerability, the immense diversity of the RIFIN and STEVOR families has so far precluded the comprehensive study of these antigens in clinical infections. The goal of this proposal is to identify RIFIN and STEVOR subtypes that are associated with severe malaria in African children. We will obtain blood and serum samples from children with severe or non-severe malaria in Mali, Malawi, and Uganda, representing three regions of sub-Saharan Africa with distinct malaria transmission patterns. In Aim 1, we will identify the expressed rif and stevor transcripts in individual blood samples using reference-free RNA-Seq, then compare the abundance of transcript subgroups between severe and non-severe malaria. In Aim 2, we will profile antibody responses against a comprehensive microarray of RIFIN and STEVOR variants to identify immune “gaps” in children with severe malaria compared to non-severe malaria. RIFIN and STEVOR antigen subtypes that were preferentially expressed and/or not serorecognized in severe malaria infections may be important mediators of pathogenesis. RIFINs that predominate in severe cases with blood type A may be critical aspects of this group’s vulnerability. The proposed aims will help clarify the role of RIFINs and STEVORs in severe malaria pathogenesis and inform the development of tailored vaccines and therapeutics to protect the most at-risk children in sub-Saharan Africa. The applicant will develop and apply hands-on skills in transcriptomics, immunoepidemiology, and international clinical research design and management, critical to his intended career as a 21st century molecular epidemiologist.